Shigella flexneri is a Gram-negative bacterial pathogen that causes bacillary dysentery in humans by infecting epithelial cells of the colon. Shigella primarily infects intestinal epithelial cells (IECs) (Jung et al., 1995). Shigella expresses several proteins that provide a mechanism for delivering effectors that induce bacterial uptake into the host cell via phagocytosis. These proteins form a type III secretion system (TTSS) and are encoded by a 220-kb virulence plasmid. Shigella bacteria then gain access to the cytoplasm by lysing the phagocytic vacuole and then expressing a motility phenotype that allows infection of other cells nearby.
To establish a successful infection, Shigella must finely regulate the host's immune response, especially those responses leading to inflammation. In contrast to Salmonella typhimurium, Shigella is inefficient at invading the apical pole of polarized IEC. Instead, Shigella requires transmigration of polymorphonuclear leucocytes (PMN) to disrupt the epithelial barrier, facilitating cell invasion via the basolateral pole of epithelial cells (Perdomo et al., 1994). The host's inflammatory response, facilitated by cells of the innate immune system, attracts PMNs to the site of inflammation. Therefore, triggering inflammation at the early stage of infection is required for cell invasion by Shigella. Bacteria that reach the intracellular compartment of IEC grow and spread from cell to cell, protected from host immune defences. But infected IEC play a large role in the inflammatory process, both as sentinels that detect bacterial invasion and as a major source of mediators, particulary cytokines and chemokines that mediate the inflammatory response. These mediators include cytokines and chemokines that initiate and orchestrate mucosal inflammation (Jung et al., 1995). Bacterial recognition by IEC occurs essentially intracellularly via a cytosolic molecule, Nod1/CARD4 that senses a microbial motif, the peptidoglycan (Girardin et al., 2003). Nod1 activation induces other proinflammatory signalling pathways including NF-κB and c-Jun N-terminal kinase (JNK) that lead to the expression of chemokines (Philpott et al., 2000), such as interleukin 8 (IL-8). These chemokines are crucial for pathogen eradication (Sansonetti et al., 1999). Thus, triggering excessive inflammation is detrimental to Shigella's survival in the host. To survive, this bacteria has evolved strategies for modulating transcription of proinflammatory genes.
Although plant and animal pathogens have developed various strategies for suppressing immunity, translocation of effector proteins via a TTSS is a mechanism by which many bacterial pathogens take control of the host innate immune response. The Shigella type III secreted OspG molecule has been shown to antagonize degradation of IκB-α by blocking its ubiquitinylation, thus demonstrating the potential of the microorganism to regulate the inflammatory response (Kim et al., 2005). Some TTSS effectors like YopE, T, and H from Yersinina pseudo tuberculosis primarily target actin polymerization as a way to escape phagocytosis (Cornelis, 2002), and other TTSS effectors suppress proinflammatory defense responses mediated by the innate immune response. In the latter case, many of these effectors are cysteine proteases that target essential components of defence signalling pathways. For example, the Pseudomonas syringae effector AvRpt2 initiates elimination of the Arabidopsis RIN4 protein, a regulator of basal defence (Axtell and Staskawicz, 2003). Other effectors induce reversible protein modifications: YopJ/P/AvrBsT represent a family of cysteine proteases that cleave the carboxy-terminus of the ubiquitin-like protein SUMO from the target proteins, and thereby interfere with multiple signalling pathways (Orth et al., 2000). YopJ also acetylates various kinases in their activation loop domains, thereby interfering with multiple signalling pathways (Mukherjec et al., 2006). The mechanisms behind how these effectors modify expression of specific host genes is currently unknown.